Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues

J Enzyme Inhib Med Chem. 2018 Dec;33(1):794-803. doi: 10.1080/14756366.2018.1458030.

Abstract

Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity.

Keywords: X-ray Crystallography; acetylcholinesterase; donepezil analogues; inhibition kinetics; β-secretase-1.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Donepezil
  • Dose-Response Relationship, Drug
  • Indans / chemistry
  • Indans / pharmacology*
  • Kinetics
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship
  • Torpedo

Substances

  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Acetylcholinesterase

Grant support

Nutramed SCaRL, actuator of the Project PON03PE_00078_1 and PON03PE_00078_1/F1, is acknowledged for the financial support.